Catalytic Epoxidation of 3-Carene and Limonene with Aqueous Hydrogen Peroxide, and Selective Synthesis of Α-Pinene Epoxide from Turpentine

catalysts

Article Catalytic Epoxidation of 3-Carene and Limonene with Aqueous Hydrogen Peroxide, and Selective Synthesis of α-Pinene Epoxide from Turpentine

Vladislav V. Fomenko * , Sergey S. Laev and Nariman F. Salakhutdinov

N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry Siberian Branch of RAS, 9 Lavrentiev Avenue, 630090 Novosibirsk, Russia; [email protected] (S.S.L.); [email protected] (N.F.S.) * Correspondence: [email protected]; Tel.: +7-383-330-97-47

Abstract: The epoxidation of turpentine (technical α-pinene), 3-carene, and limonene with aqueous hydrogen peroxide was studied in a new catalytic system employing manganese sulfate, salicylic acid, sodium bicarbonate, and acetonitrile, as a polar solvent. The proposed approach makes it possible to carry out a “chemical separation” of turpentine components, yielding valuable individual derivatives of monoterpenes without the need to isolate individual monoterpene reagents. Specific methods have been developed for the production of α-pinene epoxide, 3-carene epoxide, limonene diepoxide, as well as for two related compounds: 3-carene-5-one and 3-carene-2,5-dione. Keywords: epoxidation; turpentine; α-pinene; α-pinene epoxide; 3-carene; 3-carene epoxide; limonene; Citation: Fomenko, V.V.; Laev, S.S.; limonene diepoxide; aqueous hydrogen peroxide Salakhutdinov, N.F. Catalytic Epoxidation of 3-Carene and Limonene with Aqueous Hydrogen Peroxide, and Selective Synthesis of 1. Introduction α-Pinene Epoxide from Turpentine. Catalysts 2021, 11, 436. https:// An epoxidation reaction is one of the important methods for the functionalization of doi.org/10.3390/catal11040436 terpenes, with established industrial applications. Monoterpenes obtained from widely available and renewable raw plant materials are of particular interest, as they are starting Academic Editors: compounds for the production of valuable synthons. The most easily accessible natural Sébastien Leveneur, Vincenzo Russo, monoterpenes are β-pinene, α-pinene 1, 3-carene 2, and limonene 3. The epoxides of these Pasi Tolvanen, Broggini Gianluigi and terpenes can be used for the synthesis of intermediates used in various fragrance, perfumery Victorio Cadierno and pharmaceutical preparations [1,2], as well as in substances having a sweet taste [3]. Another promising use of α-pinene epoxide 4 is its transformation into pinocarveol and Received: 5 March 2021 3-pinanone [4]. Additionally, 3-carene epoxide 5 can be used to obtain carandiols [5]. One Accepted: 25 March 2021 of the limonene epoxides has recently been used as a source of chirality in the synthesis of Published: 29 March 2021 methylphosphonate oligonucleotides [6]. The epoxidation of β-pinene, α-pinene 1, 3-carene 2, and limonene 3 has been reviewed Publisher’s Note: MDPI stays neutral in the literature [7]. Currently, organic peracids and organic peroxides as double bond with regard to jurisdictional claims in oxidizers are being more often replaced by ordinary aqueous hydrogen peroxide. This published maps and institutional affil- oxidizing agent is readily available, environmentally friendly, and practically waste-free. iations. For sterically hindered α-pinene 1, low reactivity, low conversion, and low yield of epoxide 4 are often observed [7]. Different oxidizing agents may be used: oxygen with additives of cobalt (II) complexes [8,9], air as an oxygen source [10,11], sodium hypochlorite [12], meta-chloroperbenzoic acid [13], and hydrogen peroxide at various concentrations [13–17]. Copyright: © 2021 by the authors. In at least one instance [14], epoxidation of α-pinene 1 was achieved by the action of 30% Licensee MDPI, Basel, Switzerland. hydrogen peroxide (10 equivalents) in the presence of manganese sulfate (0.01 equiv.), This article is an open access article and NaHCO3 in an aqueous solution of dimethylformamide (DMF). The resulting yield distributed under the terms and of epoxide 4 was 54%, but the reaction times were significant and the isolation of the conditions of the Creative Commons product challenging, as it requires a high-boiling solvent. A similar situation is described in Attribution (CC BY) license (https:// another work [16]. Recently [18–23], other methods of epoxidation of α-pinene 1 have been creativecommons.org/licenses/by/ 4.0/). described that rely, in particular, on catalysts immobilized on magnetic particles [21,22].

Catalysts 2021, 11, 436. https://doi.org/10.3390/catal11040436 https://www.mdpi.com/journal/catalysts Catalysts 2021, 11, 436 2 of 8

3-Carene 2 is usually referred to as an olefin that readily participates in the epoxidation reaction [7]. As oxidizing agents, it is possible to use peracetic acid [5,24] or hydrogen peroxide [5,15,17,25] at various concentrations and at different temperatures. In the oxidation of 3-carene 2 with 35% hydrogen peroxide in the presence of a rhenium catalyst at room temperature [25], the yield of 3-carene epoxide 5 was 75%. However, the required catalyst is expensive and hard to find, and the use of a toxic pyridine is clearly a drawback. The oxidation of limonene 3 with hydrogen peroxide has received a lot of attention in the literature [7]. However, it should be noted that monoepoxidations, at the double bond in the ring and in the side chain, require difficult-to-find and expensive catalysts: molybdenum [26] and vanadium [27], respectively. Monoepoxidation of limonene has also been described [23,28–32]. The use of 60% hydrogen peroxide and of a conventional catalyst—chromatography grade aluminum oxide—leads to the formation of a mixture of both mono derivatives of limonene and its diepoxide—the reaction requiring the creation of an inert atmosphere [33]. Our interest was drawn to the epoxidation of limonene 3 by the action of 35% aqueous hydrogen peroxide in the presence of methyltrioxorenium [1]. To obtain a 90% content of limonene diepoxide 8 in the reaction mixture, we employed a 3.4-fold molar amount of hydrogen peroxide and 1 molar percent of the catalyst was used; the reaction was carried out for 40 h at 0 ◦C;. In our previous communication [34], we studied the epoxidation of β-pinene with hydrogen peroxide in a reaction mixture containing water, sodium bicarbonate, and manganese salts. Methanol, DMF, and acetonitrile were used as the required polar organic solvents, and it was found that the reaction was accelerated by the addition of salicylic acid. Optimum epoxidation was obtained in the presence of acetonitrile, sodium bicarbonate, manganese sulfate, and salicylic acid during oxidation with 35%–38% aqueous hydrogen peroxide at 18–22 ◦C. A quantitative tandem 1H NMR-GLC method was also developed in order to determine the content of β-pinene and its labile epoxide. In this work, we ex- tended the application of our catalytic system to other monoterpenes: α-pinene 1, 3-carene 2, and limonene 3. We also developed methods for the preparation of epoxides of these monoterpenes, and selectively obtained α-pinene 4 epoxide from turpentine.

2. Results and Discussion Our objective was to develop a simple, economical, and technologically sound method to produce α-pinene epoxide 4. To this aim, we epoxidized turpentine (technical α-pinene 1), which contained ~ 75% of the main substance, according to the combined data obtained by GLC and gas chromatography-mass spectrometry [34]. The cost of the technical product is about two orders of magnitude lower than that of commercial α-pinene 1. The strategy to achieve this result consisted of setting up a gradual interaction of technical α-pinene 1 with 36% aqueous hydrogen peroxide in aqueous acetonitrile in the presence of a catalytic system, which included manganese sulfate, bicarbonate sodium and salicylic acid (Scheme1 ). Hydrogen peroxide was used in a tenfold molar amount, and manganese sulfate was used in an amount of 2 percent molar amount relative to the loaded substrate. The products of interest—α-pinene epoxide 4, unreacted α-pinene 1, side monoterpenes and their oxidation products—were recovered from the reaction mixture using methylene chloride. After concentrating the extract, α-pinene epoxide 4 was isolated by vacuum distillation in 30% yield. The epoxidation system has a typical selectivity for epoxidation with peracids, so the usual selectivity is observed for α-pinene, namely 2,3-epoxy-cis-pinan 4 is formed. A fraction with a high content of α-pinene 1 was also isolated, which was then subjected to reoxidation using the above procedure. The composition of the reaction mixtures and the structures of the obtained compounds were determined by 1H NMR, GLC and gas chromatography-mass spectrometry, and by comparing the spectra with those described earlier in the literature [35]. Catalysts 2021, 11, x FOR PEER REVIEW 3 of 8

Catalysts 2021, 11, x FOR PEER REVIEW 3 of 8

determined by 1H NMR, GLC and gas chromatography-mass spectrometry, and by com- Catalysts 2021, 11, 436 paring the spectra with those described earlier in the literature [35]. 3 of 8 determined by 1H NMR, GLC and gas chromatography-mass spectrometry, and by comparing the spectra with those described earlier in the literature [35].

Scheme 1. Preparation of α-pinene epoxide 4 by epoxidation of α-pinene 1 of turpentine. Scheme 1.1. Preparation of αα-pinene-pinene epoxideepoxide 44 byby epoxidationepoxidation ofof αα-pinene-pinene 11 ofof turpentine.turpentine. In addition to its simplicity, the proposed method for producing epoxide 4 offers two advantages: (i), the epoxidation of α-pinene 1 is achieved by the action of simple, cheap, InIn additionaddition toto its simplicity, thethe proposedproposed methodmethod forfor producingproducing epoxideepoxide 44 offersoffers twotwo and commercially available reagents, and (ii), inexpensive technical α-pinene is used as advantages: (i), the epoxidation of α-pinene 1 is achieved by the actionaction ofof simple,simple, cheap,cheap, the starting compound. Although, in our work, we did not use the distillation residue and commerciallycommercially availableavailable reagents,reagents, andand (ii),(ii), inexpensiveinexpensive technicaltechnical αα-pinene-pinene isis usedused asas containing valuable products of the transformation of β-pinene, 3-carene, and limonene; thethe startingstarting compound.compound. Although, in our work,work, we diddid notnot useuse thethe distillationdistillation residueresidue they can be separated using vacuum distillation or chromatography. containingcontaining valuablevaluable productsproducts ofof thethe transformationtransformation ofof ββ-pinene,-pinene, 3-carene,3-carene, andand limonene;limonene; Epoxidation of 3-carene 2 with 36% aqueous hydrogen peroxide was carried out in theythey cancan bebe separatedseparated usingusing vacuumvacuum distillationdistillation oror chromatography.chromatography. the presence of the same catalytic system, consisting of manganese sulfate (2 percent mo- Epoxidation of 3-carene 3-carene 2 2 with with 36% 36% aqueous aqueous hydrogen hydrogen peroxide peroxide was was carried carried out out in lar), sodium bicarbonate, and salicylic acid. The most complete conversion of 3-carene 2 inthe the presence presence of the of the same same catalytic catalytic system, system, consisting consisting of manganese of manganese sulfate sulfate (2 percent (2 percent mo- was achieved using approximately ten times the amount of hydrogen peroxide. As in the molar),lar), sodium sodium bicarbonate, bicarbonate, and and salicylic salicylic acid. acid. The The most most complete complete conversion conversion of 3-carene 22 previous case, the epoxidation system has a typical selectivity for epoxidation with perac- waswas achievedachieved usingusing approximatelyapproximately tenten timestimes thethe amountamount ofof hydrogenhydrogen peroxide.peroxide. AsAs inin thethe previousids, so the case, usual the epoxidationselectivity is system observed has afor typical 3-carene, selectivity namely for epoxidationtrans-3,4-epoxy-caran with peracids, 5 is previous case, the epoxidation system has a typical selectivity for epoxidation with perac- soformed. the usual Epoxide selectivity 5, together is observed with fortraces 3-carene, of 3-carene namely 2 trans-3,4-epoxy-caranand by-products of allylic 5 is formed. oxida- ids, so the usual selectivity is observed for 3-carene, namely trans-3,4-epoxy-caran 5 is Epoxidetion—3-carene-5-one 5, together with 6 and traces 3-carene-2,5-dione of 3-carene 2 and 7 by-products (Scheme 2)—were of allylic extracted oxidation—3-carene- with meth- formed. Epoxide 5, together with traces of 3-carene 2 and by-products of allylic oxida- 5-oneylene 6chloride. and 3-carene-2,5-dione The formation 7 of (Scheme compounds2)—were 6 and extracted 7 was with previously methylene noted chloride. during The the tion—3-carene-5-one 6 and 3-carene-2,5-dione 7 (Scheme 2)—were extracted with meth- formationcatalytic oxidation of compounds of 3-carene 6 and 2 7in was the previouslypresence of noted a cobalt during catalyst the catalytic[36]. The oxidationobtained ex- of ylene chloride. The formation of compounds 6 and 7 was previously noted during the 3-carenetract was 2 concentrated, in the presence and of athe cobalt 3-carene catalyst epox [36ide]. The 5 was obtained isolated extract by vacuum was concentrated, distillation catalytic oxidation of 3-carene 2 in the presence of a cobalt catalyst [36]. The obtained ex- andwith the a yield 3-carene of 47%. epoxide The 3-carene-5-one 5 was isolated 6 by and vacuum 3-carene-2,5-dione distillation with 7 were a yield isolated of 47%. from The the tract was concentrated, and the 3-carene epoxide 5 was isolated by vacuum distillation 3-carene-5-onedistillation residue 6 and by 3-carene-2,5-dione C-18 reverse phase7 chromatographywere isolated from in 13% the distillationand 7% yields, residue respec- by with a yield of 47%. The 3-carene-5-one 6 and 3-carene-2,5-dione 7 were isolated from the C-18tively. reverse The composition phase chromatography of the reaction in 13% mixt andures 7% and yields, the structure respectively. of the The obtained composition com- distillation residue by C-18 reverse phase chromatography in 13% and 7% yields, respec- ofpounds the reaction were established mixtures and on the the structure basis of ofanalysis the obtained by 1H NMR, compounds GLC, wereand gas established chromatog- on tively. The composition of the reaction mixtures and the structure of the obtained com- theraphy-mass basis of analysis spectrometry; by 1H NMR,the 1H GLC,NMR and spectrum gas chromatography-mass of epoxide 5 coincided spectrometry; with that pub- the pounds were established on the basis of analysis by 1H NMR, GLC, and gas chromatog- 1lishedH NMR earlier spectrum [25]. of epoxide 5 coincided with that published earlier [25]. raphy-mass spectrometry; the 1H NMR spectrum of epoxide 5 coincided with that published earlier [25].

SchemeScheme 2.2. Oxidation of of 3-carene 3-carene 2 2 in in a acatalytic catalytic system system consisting consisting of ofmanganese manganese sulfate sulfate (2 mole (2 mole percent),percent), sodiumsodium bicarbonate,bicarbonate, andand salicylicsalicylic acidacid inin acetonitrile.acetonitrile. Scheme 2. Oxidation of 3-carene 2 in a catalytic system consisting of manganese sulfate (2 mole percent), sodium bicarbonate, and salicylic acid in acetonitrile. EpoxidationEpoxidation ofof limonenelimonene 33 withwith 33%33% aqueousaqueous hydrogenhydrogen peroxideperoxide waswas carriedcarried outout inin thethe samesame catalyticcatalytic system,system, usingusing ten-foldten-fold molarmolar amountsamounts ofof hydrogenhydrogen peroxideperoxide andand twotwo Epoxidation of limonene 3 with 33% aqueous hydrogen peroxide was carried out in percentpercent molarmolar manganesemanganese sulfatesulfate relativerelative toto thethe loadedloaded substrate.substrate. TheThe systemsystem waswas highlyhighly the same catalytic system, using ten-fold molar amounts of hydrogen peroxide and two activeactive andand epoxidationepoxidation proceeded proceeded exhaustively, exhaustively, with with high high yields yields of theof the desired desired diepoxides. diepox- percent molar manganese sulfate relative to the loaded substrate. The system was highly Limoneneides. Limonene diepoxide diepoxide 8 was 8 recovered was recovered from thefrom partially the partially evaporated evaporated reaction reaction mixture mixture with active and epoxidation proceeded exhaustively, with high yields of the desired diepox- methylenewith methylene chloride, chloride, the extract the extract was concentrated,was concentrated, and pureand limonenepure limonene diepoxide diepoxide 8 was 8 ides. Limonene diepoxide 8 was recovered from the partially evaporated1 reaction mixture isolatedwas isolated in an in 87% an 87% yield yield (Scheme (Schem3)e (purity 3) (purity was was determined determined using usingH 1H NMR NMR and and GLCGLC methods).with methylene The replacement chloride, the of acetonitrileextract was withconcentrated, DMF or methanol and pure led limonene to the appearance diepoxide of 8 methods). The replacement of acetonitrile with DMF or methanol led to1 the appearance of monoepoxidationwas isolated in an products87% yield in (Schem the reactione 3) (purity mixture, was and determined the yield ofusing diepoxide H NMR 8 decreased and GLC downmethods). to 55%. The replacement of acetonitrile with DMF or methanol led to the appearance of

Catalysts 2021, 11, x FOR PEER REVIEW 4 of 8

Catalysts 2021, 11, 436 4 of 8 monoepoxidation products in the reaction mixture, and the yield of diepoxide 8 decreased down to 55%.

SchemeScheme 3.3. PreparationPreparation ofof limonenelimonene diepoxidediepoxide 88 byby epoxidationepoxidation ofof limonenelimonene 3.3.

1 BasedBased onon 1H NMR data, and by comparison withwith publishedpublished datadata [[37,38],37,38], thethe limonenelimonene diepoxidediepoxide 88 obtainedobtained inin ourour workwork consistsconsists ofof stereoisomersstereoisomers 1S,2R,4R,8S,1S,2R,4R,8S, 1S,2R,4R,8R,1S,2R,4R,8R, 1R,2S,4R,8S,1R,2S,4R,8S, andand 1R,2S,4R,8R,1R,2S,4R,8R, whichwhich areare presentpresent inin thethe mixturemixture inin aa ratioratio ofof 1.4:1.0:2.0:1.5.1.4:1.0:2.0:1.5. WeWe diddid not observe observe any any significant significant differences differences inin the the composition composition of the of themixtures mixtures of lim- of limoneneonene diepoxides diepoxides from from differen differentt syntheses. syntheses. At the At same the time, same enrichment time, enrichment in some in isomers some isomerscould be could observed be observed during distillation. during distillation. We did Wenot didobserve not observe isomerization isomerization of isomers of isomers of lim- ofonene limonene diepoxides diepoxides into each into other each when other whenthey were they kept were with kept a withcatalytic a catalytic system, system, or during or duringdistillation. distillation. InIn conclusion,conclusion, wewe havehave developeddeveloped aa catalyticcatalytic systemsystem forfor thethe epoxidationepoxidation ofof monoter-monoter- α penespenes andand synthesissynthesis ofof α-pinene-pinene epoxideepoxide 4,4, 3-carene3-carene epoxideepoxide 5,5, limonenelimonene diepoxidediepoxide 8,8, asas wellwell asas sideside compounds—3-carene-5-onecompounds—3-carene-5-one 66 andand 3-carene-2,5-dione3-carene-2,5 -dione 7. 7. OptimalOptimal conditionsconditions withwith goodgood syntheticsynthetic resultsresults werewere obtainedobtained byby allowingallowing thethe monoterpenemonoterpene toto interactinteract withwith 33%–38% aqueous hydrogen peroxide in an aqueous solution of acetonitrile in the presence 33%–38% aqueous hydrogen peroxide in an aqueous solution of acetonitrile in the pres- of a catalytic system at a temperature of 18–25 ◦C. A distinct advantage of the proposed ence of a catalytic system at a temperature of 18–25 °C. A distinct advantage of the pro- method is the possible selective oxidation of turpentine with the isolation of valuable indi- posed method is the possible selective oxidation of turpentine with the isolation of valu- vidual products, followed by a recovery of the distillation residue and repeated oxidation able individual products, followed by a recovery of the distillation residue and repeated cycles in the same catalytic system. oxidation cycles in the same catalytic system. 3. Materials and Methods 3. Materials and Methods 1H NMR spectra were recorded on a Bruker DRX-500 (Bruker BioSpin, Rheinstetten, 1 Germany)H NMR and spectra AV-400 were spectrometers recorded on with a Bruker an operating DRX-500 frequency (Bruker BioS ofpin, 500.13 Rheinstetten, MHz and Germany) and AV-400 spectrometers with an operating frequency of 500.13 MHz and 400.134 MHz for solutions in CDCl3, using chloroform signals as an internal standard. GLC analysis400.134 MHz was performed for solutions on ain 7820A CDCl3 chromatograph, using chloroform (Agilent signals Technologies, as an internal Santa standard. Clara, CA,GLC US) analysis with a was flame performed ionization on detector a 7820A and ch anromatograph HP-5 capillary (Agilent column Technologies, (0.25 mm × 30 Santa m × 0.25Clara,µm), CA, carrier USA) gas with helium, a flame rate ionization of 2 mL/min. detector Analysis and an by HP-5 gas chromatography-mass capillary column (0.25 spec- mm trometry× 30 m × 0.25 was μ performedm), carrier on gas an helium, Agilent rate 7890A of 2 instrumentmL/min. Analysis with an by Agilent gas chromatography- 5975C (Agilent Technologies,mass spectrometry Santa was Clara, performed CA, US) on quadrupole an Agilent mass 7890A detector, instrument an HP-5MS with an quartz Agilent column 5975C (0.25(Agilent mm Technologies,× 30 m × 0.25 Santaµm), andClara, an HP-5973NCA, USA) gasquadrupole chromatography-mass mass detector, spectrometer an HP-5MS (Agilentquartz column Technologies) (0.25 mm with × 30 a columnm × 0.25 HP-5MS. μm), and an HP-5973N gas chromatography-mass spectrometerQuantitative (Agilent analysis Technologies) by GLC was with performed a column on HP-5MS. an HP 5890 Series chromatograph (Hewlett-PackardQuantitative Company,analysis by Palo GLC Alto, was CA, performed US) with on a katharometer an HP 5890 Series and an chromatograph HP-5 capillary column,(Hewlett-Packard 30 m long, Company, 0.53 mm inner Palo diameter,Alto, CA, and USA) a stationary with a katharometer phase layer withand an a thickness HP-5 ca- ofpillary (block column, copolymer 30 m of long, dimethylpolysiloxane 0.53 mm inner diameter, and phenylpolysiloxane) and a stationary 2.65 phaseµm; layer evaporator with a temperaturethickness of 300(block◦C, copolymer detector temperature: of dimethylpolysiloxane 280 ◦C, initial columnand phenylpolysiloxane) temperature 40 ◦C 2.65 (2 min), μm; heatingevaporator at a ratetemperature of 5 deg/min 300 ° upС, todetector 50 ◦C, 10temperature: deg/min up 280 to 70°С◦, C,initial 20 deg/min column uptemperature to 280 ◦C, isotherm40 °С (2 min), at 280 heating◦C, total at a analysis rate of 5 time: deg/min 26.5 up min; to 50 carrier °С, 10 gas-helium, deg/min up flow to 70 rate-5 °С, 20 mL/min, deg/min splitup to ratio 280 after°С, isotherm the evaporator-10. at 280 °С, total analysis time: 26.5 min; carrier gas-helium, flow rate-5Technical mL/min,α split-pinene ratio (76%), after 3-carenethe evaporator (95%), - limonene 10. (95%), and commercial reagents wereTechnical used. Solvents α-pinene were (76%), prepared 3-carene according (95%), to limonene standard (95%), procedures. and commercial reagents were1 HNMRused. Solvents and 13CNMR were prepared spectra for according 8, 1HNMR to standard spectra for procedures. 2, 5, 6, GLC-MS spectra for 4, 6, 7 are1HNMR presented and in13CNMR Supplementary. spectra for 8, 1HNMR spectra for 2, 5, 6, GLC-MS spectra for 4, 6, 7 are presented in Supplementary. 3.1. Preparation of α-Pinene Epoxide 4 in Aqueous Acetonitrile The reaction was carried out in a glass reactor with a mechanical rotating stirrer, thermometer, and a dropping funnel with back pressure for supplying liquid with vigorous

Catalysts 2021, 11, 436 5 of 8

stirring. The following reagents were loaded: 34.0 g (190 mmol) of turpentine (technical α-pinene 1) (according to combined GLC and gas chromatography-mass spectrometry analysis, it contained ~ 75% α-pinene 1, ~ 5% β-pinene, ~ 14% 3-carene 2, ~ 1% camphene, ~ 4% limonene 3), 250 mL acetonitrile, 0.6 g (4.0 mmol) anhydrous manganese sulfate, and 1.1 g (8.0 mmol) of salicylic acid. A mixture of 280 mL of 0.4 M sodium bicarbonate solution and 166 mL (2.0 mol) of 36% hydrogen peroxide was uniformly fed into the reactor over a period of 4 hours, maintaining a temperature between 20 and 25 ◦ C. The mixture was stirred for an additional 2 h and subsequently treated with 100 mL methylene chloride 3 times. The extract was washed with water, dried, and the solvent was distilled off in vacuum (~ 20 mm Hg) at a temperature below 25 ◦C. A total of 31.5 g (>80%) of the crude product was obtained. Based on 1H NMR, GLC and gas chromatography-mass spectrometry analyses, the crude product contained 46% of α-pinene epoxide 4 and 32% of α-pinene 1. The distilled solvent containing trace amounts of α-pinene was used for extraction in the next cycle of epoxide 4 preparation. The crude product was subjected to distillation with a reﬂux condenser at 10 mm Hg. with a cooled trap. Fraction 1 was distilled off at temperatures up to 75 ◦C (cube) and 40–50 ◦C (in vapors), fraction 2—at temperatures up to 90 ◦C (cube) and 50–70 ◦C (in vapors). The initial mixture (31.5 g) was fractioned as follows: fraction 1 (9.8 g) containing 62% of α-pinene 1 and 10% of α-pinene epoxide 4; fraction 2 (11.3 g) containing 85% of α-pinene epoxide 4, and the distillation residue (6.0 g). Fraction 1 was used in the next cycle for the preparation of epoxide 4; the distillation residue containing a number of valuable products of the transformation of β-pinene, 3-carene, and limonene was not used in this work. Repeated vacuum distillation under the same conditions of fraction 2 (11.3 g) yielded 8.5 g of the target product containing 93% of α-pinene epoxide 4. The total yield 1 of epoxide 4 was 30%. The H NMR spectrum (CDCl3) δ, ppm comprised the following 8 9 10 peaks: 0.92 s (3H, C H3), 1.28 s (3H, C H3), 1.34 s (3H, C H3), 1.62 d (1H), 1.69–1.74 m (1H), 1.85–2.01 m (4H), and 3.03 dd (1H, C3H).

3.2. Preparation of 3-Carene Epoxide 5, 3-Carene-5-One 6 and 3-Carene-2,5-Dione 7 in Aqueous Acetonitrile The reaction was carried out in a glass reactor with a mechanical, intensively rotating stirrer, thermometer and a nozzle for liquid supply with vigorous stirring. The following reagents were loaded: 2.30 g (16.0 mmol) of 95% 3-carene 2, 26.5 mL of acetonitrile, 0.048 g (0.32 mmol) of anhydrous manganese sulfate, and 0.088 g (0.64 mmol) of salicylic acid. A cooled mixture of 23.2 mL of 0.4 M sodium bicarbonate solution and 13.2 mL of 36% aqueous hydrogen peroxide was uniformly fed into the reactor over a period of 2 hours, maintaining the temperature between 18 and 22 ◦C. The mixture was stirred at this temperature for an additional 2 hours, and subsequently treated with 10 mL methylene chloride 3 times. The extract was washed with water, dried, and the solvent was then distilled off in a vacuum (~ 20 mm Hg) at a temperature below 25 ◦C. A total 2.19 g (~ 85%) of crude product was obtained. Based on 1H NMR, GLC, and gas chromatography-mass spectrometry analyses, the crude product contained 67% 3-carene epoxide 5, 1% 3-carene 2, 15% 3-carene-5-one 6, 8% 3-carene- 2,5-dione 7 and 9% unidentified impurities. The distilled-off solvent containing traces of 3-carene 2 and epoxide 5 was used for extraction in the next cycle for preparing epoxide 5. The crude product was subjected to distillation with a reflux condenser at 5 mm Hg. with a cooled trap. The initial mixture contained 67% of 3-carene epoxide 5. Epoxide 5 was distilled off at temperatures up to 90 ◦C (cube) and 45–60 ◦C (in vapors). A total of 1.16 g of the target product was obtained from the 2.19 g of the initial mixture. It contained 90% of epoxide 5, 2% of 3-carene 2, and unidentified compounds, as well as 0.91 g distillation residue. The 1H NMR spectrum of the target product corresponded to 1 the spectrum of 3-carene epoxide 5. The H NMR spectrum (CDCl3) δ, ppm comprised the following peaks: 0.42 ddd (1H, C1H or C6H), 0.49 ddd (1 H, C1H or C6H), 0.70 s (3H, 8 9 10 2 5 C H3), 0.98 s (3H, C H3), 1.25 s (3H, C H3), 1.47 dd, (1H, C H), 1.61 dt (1H, C H), 2.11 dd Catalysts 2021, 11, 436 6 of 8

(1H, C2H), 2.26 ddd, (1H, C5H), and 2.80 t (1H, C4H). The total yield of 3-carene epoxide 5 per 3-carene 2 was 47%. A fraction of the distillation residue (0.23 g) was subjected to C-18 reverse phase chromatography using a LiChrosorb®RP-18 (10 µm) column (MERCK KGAA, Darmstadt, Germany) (eluent-aqueous methanol, the gradient of methanol concentration varied from 35% to 55% by volume). The fractions from the GLC separations that contained individual compounds 6 and 7 were collected. Methanol was distilled off in a water-jet pump vacuum (~ 20 mm Hg) at room temperature, and the aqueous residue was extracted with diethyl ether. After the distillation of ether, 0.078 g of 3-carene-5-one 6 (yield 13%) and 0.043 g of 3-carene-2,5-dione 7 (yield 7%) were obtained. The structures of the products were conﬁrmed by 1H NMR and gas chromatography-mass spectrometry. For 3-carene-5-one 1 6, the H NMR spectrum (CDCl3) δ, ppm comprised the following peaks: 0.72 m (1H, 1 8 9 6 10 C H), 1.02 s (3H, C H3), 1.18 s (3H, C H3), ~1.3 m (1H, C H), 1.83 s (3H, C H3), ~2.3 m (1H, C2H), ~2.6 m (1H, C2H), and 5.84 s (1H, C4H). For 3-carene-2,5-dione 7, the 1H NMR 8 9 spectrum (CDCl3) δ, ppm comprised the following peaks: 1.28 s (6H, C H3,C H3), 1.95 s 10 1 6 4 (3H, C H3), 2.32 m (2H, C H, C H), and 6.48 s (1H, C H).

3.3. Preparation of Limonene Epoxide 8 in Aqueous Acetonitrile The reaction was carried out in a glass reactor with a mechanical stirrer, a thermometer, and ﬁttings for loading solid and liquid reagents with vigorous stirring. The following reagents were loaded: 3.21 g (22.4 mmol) of 95% limonene, 41 mL of acetonitrile, 0.066 g (0.44 mmol) of anhydrous manganese sulfate, and 0.122 g (0.87 mmol) of salicylic acid. A cooled mixture of 30 mL of 0.4 M aqueous sodium bicarbonate solution and 21.5 mL of 33% aqueous hydrogen peroxide was uniformly fed into the reactor over a period of 3.5 hours, maintaining the temperature between 18 and 22 ◦C. The mixture was stirred at this temperature for another 15 min, and subsequently evaporated under vacuum at 25 ◦C, collecting the distillation in a cooled trap. The volume of the reaction mixture was decreased by a factor of 1.5. The evaporated reaction mixture was treated three times with 15 mL of methylene chloride. The extract was washed with water, dried, and the solvent subsequently distilled off under reduced pressure at a temperature of 25 ◦C, yielding 3.43 g (87%). Based on 1H NMR and GLC analyses, the product contained 95% limonene 1 diepoxide 8 in the form of four spatial isomers. The H NMR spectrum (CDCl3) δ, ppm 10 7 comprised the following peaks: 1.10 s, 1.11 s, 1.12 s, 1.13 s (3H, C H3), 1.19 s (3H, C H3), 9 2 2.34–2.50 m (2H, C H2), and 2.82–2.92 m (1H, C H). The azeotropic mixture of acetonitrile with water was distilled off from the reaction mixture and, to obtain limonene diepoxide, distilled methylene chloride was used in the subsequent cycles. Organic solvents may be reused in the procedures.

Supplementary Materials: The following are available online at https://www.mdpi.com/article/ 10.3390/catal11040436/s1, Figure S1: 1H-NMR compound 8, synthesis var1; Figure S2: 1H-NMR compound 8, synthesis var1 determination of the ratio of isomers; Figure S3: 1H-NMR compound 8, synthesis var2 determination of the ratio of isomers; Figure S4: 1H-NMR compound 8, synthesis var2; Figure S5: 13C-NMR compound 8, synthesis var1 domain 24.5ppm; Figure S6: 13C-NMR compound 8, synthesis var1; Figure S7: 13C-NMR compound 8, synthesis var2 domain 31ppm; Figure S8: 13C-NMR compound 8, synthesis var2; Figure S9: GLC-MS 3-carene allyl oxydation 1page CAR-3-EN-2-ONE; Figure S10: GLC-MS 3-carene allyl oxydation 2page CAR-3-EN-2-ONE; Figure S11: GLC-MS alpha-pinene epoxide distillated 1page; Figure S12: GLC-MS alpha-pinene epoxide distillated 2page; Figure S13: GLC-MS alpha-pinene epoxide mixture 1page; Figure S14: GLC-MS alpha-pinene epoxide mixture 2page; Figure S15: GLC-MS car-3-en-2,5-dione 1page; Figure S16: GLC-MS car-3-en-2,5-dione 2page; Figure S17: H-NMR 3-carene epoxide; Figure S18: H-NMR 3-carene; Figure S19: H-NMR of car-3-en-2-one; Figure S20: MS car-3-en-2-one from library. Author Contributions: All authors have made substantive intellectual contributions to this study, at the conceptional and design levels, and pertaining to the acquisition, analysis, and interpretation of data. All authors participated in the drafting and revision of the manuscript, and all have approved Catalysts 2021, 11, 436 7 of 8

the current version to be published in Catalysts Journal. Supervision and project administration was made by N.F.S. All authors have read and agreed to the published version of the manuscript. Funding: The research was supported by Russian Foundation for Basic Research (RFBR, grant 19-29-04011). Acknowledgments: Authors would like to acknowledge the Multi-Access Chemical Research Center SB RAS for spectral and analytical measurements. Conﬂicts of Interest: The authors declare no conﬂict of interest.

References 1. De Villa, A.L.P.; De Vos, D.E.; De Montes, C.C.; Jacobs, P.A. Selective epoxidation of monoterpenes with methyltrioxorhenium and H2O2. Tetrahedron Lett. 1998, 39, 8521–8524. [CrossRef] 2. Fdil, N.; Romane, A.; Allaoud, S.; Karim, A.; Castanet, Y.; Mortreux, A. Terpenic olefin epoxidation using metals acetylacetonates as catalysts. J. Mol. Catal. A 1996, 108, 15–21. [CrossRef] 3. Mori, K.; Kato, M. Synthesis and absolute configuration of (+)-hernandulcin, a new sesquiterpene with intensely sweet taste. Tetrahedron Lett. 1986, 27, 981–982. [CrossRef] 4. Scheidl, F. Katalytische Umlagerungen von α-Pinen-epoxid in Gegenwart von Aluminium-alkoxiden. Synthesis 1982, 9, 728. [CrossRef] 5. Watanabe, K.; Yamamoto, N.; Kaetsu, A.; Yamada, Y. Process for Producing 3,4-Caranediol. U.S. Patent 5608088A, 4 March 1997. 6. Xu, D.; Rivas-Bascón, N.; Padial, N.M.; Knouse, K.W.; Zheng, B.; Vantourout, J.C.; Schmidt, M.A.; Eastgate, M.D.; Baran, P.S. Enantiodivergent Formation of C−P Bonds: Synthesis of P-Chiral Phosphines and Methylphosphonate Oligonucleotides. J. Am. Chem. Soc. 2020, 142, 5785–5792. [CrossRef][PubMed] 7. Bakhvalov, O.V.; Fomenko, V.V.; Salakhutdinov, N.F. Modern Methods of Epoxidation of α- and β-Pinenes, 3-Carene and Limonene. Chem. Sustain. Dev. 2008, 16, 633–691. 8. Takai, T.; Hata, E.; Yorozu, K.; Mukaiyama, T. Cobalt(II) Complex Catalyzed Epoxidation of Olefins by Combined Use of Molecular Oxygen and Cyclic Ketones. Chem. Lett. 1992, 21, 2077. [CrossRef] 9. Zhang, H.; He, J.; Lu, X.; Yang, L.; Wang, C.; Yue, F.; Zhou, D.; Xia, Q. Fast-synthesis and catalytic property of heterogeneous Co-MOF catalysts for the epoxidation of α-pinene with air. New J. Chem. 2020, 44, 17413–17421. [CrossRef] 10. Martinez, H.; Amaya, A.A.; Paez-Mozo, E.A.; Martinez, F. Highly efficient epoxidation of α-pinene with O2 photocatalyzed by (VI) dioxoMo complex anchored on TiO2 nanotubes. Microporous Microporous Mater. 2018, 265, 202–210. [CrossRef] 11. Lu, X.H.; Lei, J.; Wei, H.L.; Ma, X.T.; Zhang, T.J.; Hu, W.; Zhou, D.; Xia, Q.H. Selectively catalytic epoxidation of α-pinene with dry air over the composite catalysts of Co–MOR(L) with Schiff-base ligands. J. Mol. Catal. A Chem. 2015, 400, 71–80. [CrossRef] 12. Elemans, J.A.A.W.; Bijsterveld, E.J.A.; Rowan, A.E.; Nolte, R.J.M. A host–guest epoxidation. Chem. Commun. 2000, 24, 2443–2444. [CrossRef] 13. Majetich, G.; Hicks, R.; Sun, G.R.; McGill, P. Carbodiimide-Promoted Olefin Epoxidation with Aqueous Hydrogen Peroxide. J. Org. Chem. 1998, 63, 2564–2573. [CrossRef][PubMed] 14. Lane, B.S.; Burgess, K. A cheap, catalytic, scalable, and environmentally benign method for alkene epoxidations. J. Am. Chem. Soc. 2001, 123, 2933–2934. [CrossRef] 15. Mouret, A.; Leclercq, L.; Muhlbauer, A.; Nardello-Rataj, V. Eco-friendly solvents and amphiphilic catalytic polyoxometalate nanoparticles: A winning combination for olefin epoxidation. Green Chem. 2014, 16, 269–278. [CrossRef] 16. Pierri, L.; Gemenetzi, A.; Mavrogiorgou, A.; Regitano, J.B.; Deligiannakis, Y.; Louloudi, M. Biochar as supporting material for heterogeneous Mn(II) catalysts: Efficient olefins epoxidation with H2O2. Mol. Catal. 2020, 489, 110946. [CrossRef] 17. Cunningham, W.B.; Tibbetts, J.D.; Hutchby, M.; Maltby, K.A.; Davidson, M.G.; Hintermair, U.; Plucinski, P.; Bull, S.D. Sustainable catalytic protocols for the solvent free epoxidation and anti-dihydroxylation of the alkene bonds of biorenewable terpene feedstocks using H2O2 as oxidant. Green Chem. 2020, 22, 513–524. [CrossRef] 18. Shi, Z.; Wu, C.; Wu, Y.; Liu, H.; Xu, G.; Deng, J.; Gu, H.; Liu, H.; Zhang, J.; Umar, A.; et al. Optimization of Epoxypinane Synthesis by Silicotungstic Acid Supported on SBA-15 Catalyst Using Response Surface Methodology. Sci. Adv. Mater. 2019, 11, 699–707. [CrossRef] 19. Bermudez, J.H.; Rojas, G.; Benitez, R.B.; Franco, J.M. Easy Epoxidation of Monoterpenes from Common Starting Materials. J. Braz. Chem. Soc. 2020, 31, 1086–1092. [CrossRef] 20. Charbonneau, L.; Foster, X.; Kaliaguine, S. Ultrasonic and Catalyst-Free Epoxidation of Limonene and Other Terpenes Using Dimethyl Dioxirane in Semibatch Conditions. ACS Sustain. Chem. Eng. 2018, 6, 12224–12231. [CrossRef] 21. Payami, F.; Bezaatpour, A.; Eskandari, H. Excellent alkene epoxidation catalytic activity of macrocyclic-based complex of dioxo-Mo(VI) on supermagnetic separable nanocatalyst. Appl. Organomet. Chem. 2018, 32, e3986. [CrossRef] 22. Akbarpour, S.; Bezaatpour, A.; Askarizadeh, E.; Amiri, M. Covalent supporting of novel dioxo-molybdenum tetradentate pyrrole-imine complex on Fe3O4 as high-efficiency nanocatalyst for selective epoxidation of olefins. Appl. Organomet. Chem. 2017, 31, e3804. [CrossRef] Catalysts 2021, 11, 436 8 of 8

23. Mirkhani, V.; Moghadam, M.; Tangestaninejad, S.; Bahramian, B. Polystyrene-bound imidazole as a heterogeneous axial ligand for Mn(salophen)Cl and its use as biomimetic alkene epoxidation and alkane hydroxylation catalyst with sodium periodate. Appl. Catal. 2006, 311, 43–50. [CrossRef] 24. Arbuzov, B.A. Research in the field of isomerization of terpene oxides. III. Isomerization of camphene, nopinene and 3-carene oxides in the Reformatsky reaction. Russ. J. Gen. Chem. 1939, 9, 255. 25. Saladino, R.; Neri, V.; Pelliccia, A.R.; Mincione, A.R. Selective epoxidation of monoterpenes with H2O2 and polymer-supported methylrheniumtrioxide systems. Tetrahedron 2003, 59, 7403–7408. [CrossRef] 26. Barlan, A.U.; Basak, A.; Yamamoto, H. Enantioselective Oxidation of Olefins Catalyzed by a Chiral Bishydroxamic Acid Complex of Molybdenum. Angew. Chem. Int. Ed. 2006, 45, 5849–5852. [CrossRef][PubMed] 27. Nakagawa, Y.; Kamata, K.; Kotani, M.; Yamaguchi, K.; Mizuno, N. Polyoxovanadometalate-Catalyzed Selective Epoxidation of Alkenes with Hydrogen Peroxid. Angew. Chem. Int. Ed. 2005, 44, 5136–5141. [CrossRef][PubMed] 28. Zhou, X.T.; Ji, H.B.; Xu, J.C.; Pei, L.X.; Wang, L.F.; Yao, X.D. Enzymatic-like mediated olefins epoxidation by molecular oxygen under mild conditions. Tetrahedron Lett. 2007, 48, 2691–2695. [CrossRef] 29. Resul MFMGFernandez, A.M.L.; Rehman, A.; Harvey, A.P. Development of a selective, solvent-free epoxidation of limonene using hydrogen peroxide and a tungsten-based catalyst. React. Chem. Eng. 2018, 3, 747–756. [CrossRef] 30. Charbonneau, L.; Foster, X.; Zhao, D.; Kaliaguine, S. Catalyst-Free Epoxidation of Limonene to Limonene Dioxide. ACS Sustain. Chem. Eng. 2018, 6, 5115–5121. [CrossRef] 31. Charbonneau, L.; Kaliaguine, S. Epoxidation of limonene over low coordination Ti in Ti-SBA-16. Appl. Catal. A Gen. 2017, 533, 1–8. [CrossRef] 32. Guidotti, M.; Psaro, R.; Batonneau-Gener, I.; Gavrilova, E. Heterogeneous Catalytic Epoxidation: High Limonene Oxide Yields by Surface Silylation of Ti-MCM-41. Chem. Eng. Technol. 2011, 34, 1924–1927. [CrossRef] 33. van Viet, M.C.A.; Mandelli, D.; Arends, I.W.C.E.; Schuchardt, U.; Sheldon, R.A. Alumina: A cheap, active and selective catalyst for epoxidations with (aqueous) hydrogen peroxide. Green Chem. 2001, 3, 243–246. [CrossRef] 34. Fomenko, V.V.; Bakhvalov, O.V.; Kollegov, V.F.; Salakhutdinov, N.F. Catalytic epoxidation of β-pinene with aqueous hydrogen peroxide. Russ. J. Gen. Chem. 2017, 87, 1675–1679. [CrossRef] 35. Tatarova, L.E.; Korchagina, D.V.; Volcho, K.P.; Salakhutdinov, N.F.; Barkhash, V.A. Reactions of Epoxides Prepared from Some Monoterpenes with Acetic Anhydride on Aluminosilicate Catalysts. Russ. J. Org. Chem. 2003, 39, 1076–1082. [CrossRef] 36. Galin, F.Z.; Kukovinets, O.S.; Shereshovets, V.V.; Safiullin, R.L.; Kukovinets, A.G.; Kabal’nova, N.N.; Kasradze, V.G.; Zaripov, R.N.; Kargapol’tseva, T.A.; Kashina, Y.A.; et al. Synthesis of 4α-Hydroxy-6,6-Dimethyl-3-Oxabicyclo[3.1.0]hex-2-one from (+)-3-Carene. Russ. J. Org. Chem. 1996, 32, 1429–1432. 37. Carman, R.M.; Klika, K.D. Determination of the Enantiomeric Composition of Limonene and Limonene-1,2-epoxide in Lemon Peel by Multidimensional Gas Chromatography with Flame-lonization Detection and Selected Ion Monitoring Mass Spectrometry. Aust. J. Chem. 1991, 44, 1803–1808. [CrossRef] 38. Soto, M.; Koschek, K. Diastereoisomeric diversity dictates reactivity of epoxy groups in limonene dioxide polymerization. Express Polym. Lett. 2018, 12, 583–589. [CrossRef]